This invention relates to a pharmaceutically active compound, a process for its production, compositions containing the compound and methods of using the compound in the treatment of certain disease states in mammals, in particular man. More specifically, the present invention relates to a charge-neutralization-complex of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid or its salt form, particularly, the methanesulfonate salt, and L-arginine. Most particularly, this invention relates to a 1:1 to a 1:3 molar charge-neutralization-complex of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid or its monomethanesulfonate salt and L-arginine (herein referred to as (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid arginyl charge-neutralization-complex or eprosartan arginyl charge-neutralization-complex), a wet granulation process for preparing said charge-neutralization-complex, compositions containing this charge-neutralization-complex, and methods of using (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid arginyl charge-neutralization-complex to block angiotensin II (AII) receptors and to treat hypertension, congestive heart failure and renal failure.
The compound (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid is known by the name eprosartan and its methanesulfate salt is known as eprosartan mesylate. Eprosartan and eprosartan mesylate are the subject of U.S. Pat. No. 5,185,351 (the ""351 patent), issued Feb. 9, 1993. This patent discloses in Example 41 a process for making the anhydrous form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate. Additionally, the ""351 patent discloses conventional techniques for formulating (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate and Examples 108-111 specifically detail the preparation of certain formulations. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
Human clinical studies indicate (E)-xcex1-[2-n-butyl-1-[(4-carboxy phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate to be safe and well tolerated even up to doses of 800 mg per day. The time to maximum concentration is between 1 to 2.5 hours in fasted state and 2.5-4 hours in fed state. (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate exhibits a mean absolute bioavailability of approximately 13%.
Surprisingly, it has been found that the arginine charge-neutralization-complex of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid or its monomethanesulfonate salt has increased lipophilicity, better dissolution profile and increased in vitro permeability through rabbit colon, when compared to the monomethanesulfonate salt. This is particularly important when formulating (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid or its monomethanesulfonate salt for therapeutic use.
The present invention provides a novel charge-neutralization-complex of L-arginine and (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid or its monomethanesulfonate salt in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure.
The present invention also provides a process for preparing (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid arginyl charge-neutralization-complex during wet granulation of the anhydrous form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with water in the presence of L-arginine.